Cardiac arrhythmias may be defined as abnormalities in the rate, regularity, or site of origin of the cardiac impulse or as disturbances in conduction which causes an abnormal sequence of activation. Arrhythmias may be classified clinically by means of the presumed site of origin (i.e. as supraventricular, including atrial and atrioventricular, arrhythmias and ventricular arrhythmias) and/or by means of rate (i.e. bradyarrhythmias (slow) and tachyarrhythmias (fast)).
In the treatment of cardiac arrhythmias, the negative outcome in clinical trials (see, for example, the outcome of the Cardiac Arrhythmia Suppression Trial (CAST) reported in New England Journal of Medicine 321, 406 (1989)) with “traditional” antiarrhythmic drugs, which act primarily by slowing the conduction velocity (class I antiarrhythmic drugs), has prompted drug development towards compounds which selectively delay cardiac repolarization, thus prolonging the QT interval. Class III antiarrhythimic drugs may be defined as drugs which prolong the trans-membrane action potential duration (which can be caused by a block of outward K+ currents or from an increase of inward ion currents) and refractoriness, without affecting cardiac conduction.
One of the key disadvantages of hitherto known drugs which act by delaying repolarization (class III or otherwise) is that they all are known to exhibit a unique form of proarrhythmia known as torsades de pointes (turning of points), which may, on occasion be fatal. From the point of view of safety, the minimisation of this phenomenon (which has also been shown to be exhibited as a result of administration of non-cardiac drugs such as phenothiazines, tricyclic antidepressants, antihistamines and antibiotics) is a key problem to be solved in the provision of effective antiarrhythmic drugs.
Antiarrhythmic drugs based on bispidines (3,7-diazabicyclo[3.3.1]nonanes), are known from inter alia international patent applications WO 91/07405 and WO 99/31100, European patent applications 306 871, 308 843 and 665 228 and U.S. Pat. Nos. 3,962,449, 4,556,662, 4,550,112, 4,459,301 and 5,468,858, as well as journal articles including inter alia: J. Med. Chem. 39, 2559, (1996); Pharmacol. Res. 24, 149 (1991); Circulation 90, 2032 (1994); and Anal. Sci. 9, 429, (1993). Compounds based on 3,7-diazabicyclo[3.3.0]octane are neither disclosed nor suggested in any of these documents.
Compounds based on 3,7-diazabicyclo[3.3.0]octane are known for use in a variety of medical applications, including, inter alia as: anti-migraine agents (as described in WO 98/06725 and WO 97/11945); antibiotics (as described in WO 97/10223 and WO 96/35691); neuroleptics (as described in WO 95/15327 and WO 95/13279); serotonin reuptake inhibitors (as described in WO 96/07656); thrombin inhibitors (as described in Helvetica Chim. Acta 83, 855 (2006), Chem. & Biol. 4, 287 (1997) and Angew. Chem. Int. Ed. Eng. 34, 1739 (1995)); and anxiolytic agents (as described in J. Med. Chem. 32, 1024 (1989)). Further, compounds based on 3,7-diazabicyclo[3.3.0]octane have been used in the treatment of, inter alia, gastrointestinal disorders (as described in DE 39 30 266 A1) and diseases caused by malfunction of the glutaminergic system (as described in WO 01/04107).
Other 3,7-diazabicyclo[3.3.0]octane compounds are known as chemical curiosities from inter alia J. Heterocyclic. Chem. 20, 321 (1983), Chem. Ber. 101, 3010 (1968), J. Chem. Soc., Perkin Trans. I 1475 (1983), Tetrahedron, Suppl. 8 Part I, 279 (1966) and J. Org. Chem. 61, 8897 (1996). Further, 3,7-bis(1-phenylethyl)-3,7-diazabicyclo[3.3.0]octane is known to be useful in controlling the enantioselectivity of reactions between Grignard reagents and aldehydes (as described in Tetrahedron 5, 569 (1994)).
None of the prior art documents mentioned above that relate to 3,7-diazabicyclo[3.3.0]octanes disclose or provide any suggestion that the compounds disclosed therein may be useful in the treatment of cardiac arrhythmias.
We have surprisingly found that a novel group of 3,7-diazabicyclo[3.3.0]-octane-based compounds exhibit electrophysiological activity, preferably class III electrophysiological activity, and are therefore expected to be useful in the treatment of cardiac arrhythmias.